Rare diseases are always a real challenge. The first test is to remember the myriads of often obscure but frequently tell-tale clinical signs that lead to suspicion for a specific disease. The next is to recognize these signs in the clinic, something that is not easy unless you are looking for them. Then there is the difficulty of figuring out the appropriate diagnostic work-up. Getting samples to the right diagnostic centers often presents a logistical problem, and when the results return, how to manage the condition. Comprehensive care is particularly challenging, due to frequently hidden comorbidities. So how are these challenges to be handled for more than 3000 rare diseases?